Macrophage-specific IEX-1 ? A Novel Mechanism in the Pathogenesis of Atherosclerosis Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the artery wall. It is the leading cause of morbidity and mortality in the US. Several immune cells are involved in genesis of atherosclerosis; however, macrophages play a central role in all stages of the disease. Emerging evidence suggests that both the quantity and phenotype of macrophages influence the inception and progression of atherosclerotic lesions. Several macrophages subsets have been identified in atherosclerotic plaques, including classically-activated (CAMs), alternatively-activated (AAMs), and Mox based on their distinct gene expression. Macrophages with CAMs-like characteristics play a crucial role in initiation of atherosclerosis by infiltrating in sub-endothelial space and promoting inflammation. They engulf lipids and become foam cell to form plaque. In contrast, AAMs-like macrophages are enriched in regressing plaques. They inhibit inflammation and exhibit reduced foam cell formation. However, the identity of bona fide factors that critically regulate macrophage phenotype remain poorly understood. As a result, there is a dearth of the effective strategies to inhibit pro-atherogenic phenotype of macrophages to reduce atherosclerosis. IEX-1 is a stress- inducible gene that is highly expressed in macrophages. Our preliminary investigation revealed that IEX-1 is essential for atherosclerosis development and that its deficiency protected mice against atherosclerosis without impacting cholesterol metabolism. Interestingly, IEX-1 deficiency reversed the phenotype of macrophages infiltrated in aorta from CAMs to a AAMs-like state, with only little effect on macrophage infiltration. AAMs- biased polarization preceded the development of atherosclerotic plaque. In the current proposal we will address the hypothesis that IEX-1 activity in macrophages is required for atherogenesis. To address this, we propose to use a novel mouse model in which IEX-1 will be selectively deleted from macrophages on ApoE- deficiency background. We will study its impact on atherosclerotic plaque formation, aortic macrophage phenotype, and inflammatory status. Furthermore, to gain a mechanistic insight into how IEX-1 contributes to atherosclerosis, we plan to investigate a role of apoptosis and glycolysis in macrophage polarization and foam cell formation, the central step in plaque formation. We will employ several pharmacological approaches to alter IEX-1 expression or glycolysis and evaluate its impact on macrophage phenotype and foam cell production. Together, these studies will advance our understanding of how macrophage phenotype regulates atherosclerosis. The results may help develop promising therapeutic or diagnostic approaches for lipid-driven inflammatory conditions such as atherosclerosis, diabetes, and obesity.